Inhibitors of serine proteases, particularly HCV NS3-NS4A protease

ABSTRACT

The present invention relates to compounds of formula I: 
                         
or pharmaceutically acceptable salts thereof that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and to processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.10/821,663, filed Apr. 9, 2004, now U.S. Pat. No. 7,365,092 entitled“Inhibitors of Serine Proteases, Particularly HCV NS3-NS4A Protease”,which claims the benefit of U.S. Provisional Application No. 60/510,317,filed Oct. 10, 2003, entitled “Inhibitors of Serine Proteases,Particularly HCV NS3-NS4A Protease”, the entire contents of theseapplications are hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds that inhibit serine proteaseactivity, particularly the activity of hepatitis C virus NS3-NS4Aprotease. As such, they act by interfering with the life cycle of thehepatitis C virus and are also useful as antiviral agents. The inventionfurther relates to pharmaceutical compositions comprising thesecompounds either for ex vivo use or for administration to a patientsuffering from HCV infection. The invention also relates to processesfor preparing the compounds and methods of treating an HCV infection ina patient by administering a pharmaceutical composition comprising acompound of this invention.

BACKGROUND OF THE INVENTION

Infection by hepatitis C virus (“HCV”) is a compelling human medicalproblem. HCV is recognized as the causative agent for most cases ofnon-A, non-B hepatitis, with an estimated human sero-prevalence of 3%globally [A. Alberti et al., “Natural History of Hepatitis C,” J.Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)]. Nearly four millionindividuals may be infected in the United States alone [M. J. Alter etal., “The Epidemiology of Viral Hepatitis in the United States,Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter“Hepatitis C Virus Infection in the United States,” J. Hepatology, 31.,(Suppl. 1), pp. 88-91 (1999)].

Upon first exposure to HCV only about 20% of infected individualsdevelop acute clinical hepatitis while others appear to resolve theinfection spontaneously. In almost 70% of instances, however, the virusestablishes a chronic infection that persists for decades [S. Iwarson,“The Natural Course of Chronic Hepatitis,” FEMS Microbiology Reviews,14, pp. 201-204 (1994); D. Lavanchy, “Global Surveillance and Control ofHepatitis C,” J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usuallyresults in recurrent and progressively worsening liver inflammation,which often leads to more severe disease states such as cirrhosis andhepatocellular carcinoma [M. C. Kew, “Hepatitis C and HepatocellularCarcinoma”, FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saitoet. al., “Hepatitis C Virus Infection is Associated with the Developmentof Hepatocellular Carcinoma,” Proc. Natl. Acad. Sci. USA, 87, pp.6547-6549 (1990)]. Unfortunately, there are no broadly effectivetreatments for the debilitating progression of chronic HCV.

The HCV genome encodes a polyprotein of 3010-3033 amino acids [Q. L.Choo, et. al., “Genetic Organization and Diversity of the Hepatitis CVirus.” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato etal., “Molecular Cloning of the Human Hepatitis C Virus Genome FromJapanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci.USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure andOrganization of the Hepatitis C Virus Genome Isolated From HumanCarriers,” J. Virol., 65, pp. 1105-1113 (1991)]. The HCV nonstructural(NS) proteins are presumed to provide the essential catalytic machineryfor viral replication. The NS proteins are derived by proteolyticcleavage of the polyprotein [R. Bartenschlager et. al., “NonstructuralProtein 3 of the Hepatitis C Virus Encodes a Serine-Type ProteinaseRequired for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67,pp. 3835-3844 (1993); A. Grakoui et. al., “Characterization of theHepatitis C Virus-Encoded Serine Proteinase: Determination ofProteinase-Dependent Polyprotein Cleavage Sites,” J. Virol., 67, pp.2832-2843 (1993); A. Grakoui et. al., “Expression and Identification ofHepatitis C Virus Polyprotein Cleavage Products,” J. Virol., 67, pp.1385-1395 (1993); L. Tomei et. al., “NS3 is a serine protease requiredfor processing of hepatitis C virus polyprotein”, J. Virol., 67, pp.4017-4026 (1993)].

The HCV NS protein 3 (NS3) contains a serine protease activity thathelps process the majority of the viral enzymes, and is thus consideredessential for viral replication and infectivity. It is known thatmutations in the yellow fever virus NS3 protease decrease viralinfectivity [Chambers, T. J. et. al., “Evidence that the N-terminalDomain of Nonstructural Protein NS3 From Yellow Fever Virus is a SerineProtease Responsible for Site-Specific Cleavages in the ViralPolyprotein”, Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. Thefirst 181 amino acids of NS3 (residues 1027-1207 of the viralpolyprotein) have been shown to contain the serine protease domain ofNS3 that processes all four downstream sites of the HCV polyprotein [C.Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-CleavageRequirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157(1994)].

The HCV NS3 serine protease and its associated cofactor, NS4A, helpsprocess all of the viral enzymes, and is thus considered essential forviral replication. This processing appears to be analogous to thatcarried out by the human immunodeficiency virus aspartyl protease, whichis also involved in viral enzyme processing. HIV protease inhibitors,which inhibit viral protein processing, are potent antiviral agents inman, indicating that interrupting this stage of the viral life cycleresults in therapeutically active agents. Consequently HCV NS3 serineprotease is also an attractive target for drug discovery.

Several potential HCV protease inhibitors have been described [PCTpublication Nos. WO 02/18369, WO 02/08244, WO 00/09558, WO 00/09543, WO99/64442, WO 99/07733, WO 99/07734, WO 99/50230, WO 98/46630, WO98/17679 and WO 97/43310, U.S. Pat. No. 5,990,276, M. Llinas-Brunet etal., Bioorg. Med. Chem. Lett., 8, pp. 1713-18 (1998); W. Han et al.,Bioorg. Med. Chem. Lett., 10, 711-13 (2000); R. Dunsdon et al., Bioorg.Med. Chem. Lett., 10, pp. 1571-79 (2000); M. Llinas-Brunet et al.,Bioorg. Med. Chem. Lett., 10, pp. 2267-70 (2000); and S. LaPlante etal., Bioorg. Med. Chem. Lett., 10, pp. 2271-74 (2000)].

Furthermore, the current understanding of HCV has not led to any othersatisfactory anti-HCV agents or treatments. Until recently, the onlyestablished therapy for HCV disease was interferon treatment. However,interferons have significant side effects [M. A. Wlaker et al.,“Hepatitis C Virus: An Overview of Current Approaches and Progress,”DDT, 4, pp. 518-29 (1999); D. Moradpour et al., “Current and EvolvingTherapies for Hepatitis C,” Eur. J. Gastroenterol. Hepatol., 11, pp.1199-1202 (1999); H. L. A. Janssen et al. “Suicide Associated withAlfa-Interferon Therapy for Chronic Viral Hepatitis,” J. Hepatol., 21,pp. 241-243 (1994); P. F. Renault et al., “Side Effects of AlphaInterferon,” Seminars in Liver Disease, 9, pp. 273-277. (1989)] andinduce long term remission in only a fraction (˜25%) of cases [O.Weiland, “Interferon Therapy in Chronic Hepatitis C Virus Infection”,FEMS Microbiol. Rev., 14, pp. 279-288 (1994)]. Recent introductions ofthe pegylated forms of interferon (PEG-Intron® and Pegasys®) and thecombination therapy of ribavirin and pegylated interferon (Rebetrol®)have resulted in only modest improvements in remission rates and onlypartial reductions in side effects. Moreover, the prospects foreffective anti-HCV vaccines remain uncertain.

Thus, there is a need for more effective anti-HCV therapies. Suchinhibitors would have therapeutic potential as protease inhibitors,particularly as serine protease inhibitors, and more particularly as HCVNS3 protease inhibitors. Specifically, such compounds may be useful asantiviral agents, particularly as anti-HCV agents.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof,wherein:R₉ and R_(9′), are each independently:

-   -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in each of R₉ and            R_(9′) are optionally replaced by O, N, NH, S, SO, or SO₂ in            a chemically stable arrangement;        -   wherein each of R₉ and R_(9′), is independently and            optionally substituted with up to 3 substituents            independently selected from J;        -   J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo,            thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy,            1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,            —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O) OR′,            —C(O)C(O)N(R′)₂, —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′,            —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂,            —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′,            —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂,            —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂,            —N(R′)C(S)N(R′)₂, —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂,            —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂,            —P(O)(OR′)₂, or —P(O)(H)(OR′); wherein;            -   each R′ is independently selected from:            -   hydrogen-,            -   (C1-C12)-aliphatic-,            -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,            -   [(C3-C10)-cycloalkyl or                -cycloalkenyl]-(C1-C12)-aliphatic-,            -   (C6-C10)-aryl-,            -   (C6-C10)-aryl-(C1-C12)aliphatic-,            -   (C3-C10)-heterocyclyl-,            -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,            -   (C5-C10)-heteroaryl-, and            -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;            -   wherein up to 5 atoms in R′ are optionally and                independently substituted with J;            -   wherein two R′ groups bound to the same atom optionally                form a 5- to 6-membered aromatic or a 3- to 7-membered                saturated or partially unsaturated ring system having up                to 3 heteroatoms independently selected from N, NH, O,                S, SO, and SO₂, wherein said ring is optionally fused to                a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl,                or a (C3-C10)heterocyclyl, wherein any ring has up to 3                substituents selected independently from J;                R₁₀, R_(10′), R₁₁, and R_(11′), are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein any ring is optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein up to 3 aliphatic carbon atoms in each of R₁₀,            R_(10′), R₁₁, and R_(11′) are optionally replaced by a            heteroatom selected from O, NH, S, SO, or SO₂ in a            chemically stable arrangement;        -   wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is            independently and optionally substituted with up to 3            substituents independently selected from J; or            R₁₀ is —OR′ and R_(10′) is H; or            R₁₀ and R_(10′) are both —OR′ or —SR′; or            R₁₀ and R_(10′) are both fluorine; or            R₁₀ and R_(10′) are optionally taken together with the            carbon atom to which they are bound to form a 5- to            7-membered saturated or partially unsaturated ring system;    -   wherein the R₁₀ and R_(10′) atoms bound to the carbon atom are        independently C(H), N, NH, O, S, SO, or SO₂;    -   wherein said ring optionally contains up to 4 heteroatoms        independently selected from N, NH, O, S, SO, and SO₂;    -   wherein any atom is optionally singly or multiply substituted        with up to 2 substituents selected independently from J; and    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J; or        R₉ and R₁₀ are optionally taken together with the ring atoms to        which they are bound to form a 5- to 6-membered aromatic or a 3-        to 7-membered saturated or partially unsaturated ring system up        to 3 heteroatoms independently selected from N, NH, O, S, SO, or        SO₂; wherein said ring system is optionally substituted with up        to 3 substituents selected independently from J; or        R₁₀ and R₁₁ are optionally taken together with the ring atoms to        which they are bound to form a 5- to 6-membered aromatic or a 3-        to 7-membered saturated or partially unsaturated ring system        having up to 3 heteroatoms independently selected from N, NH, O,        S, SO, or SO₂; wherein said ring is optionally substituted with        up to 3 substituents selected independently from J; or        R₉ and R₁₁ are optionally taken together with the ring atoms to        which they are bound to form a bridged bicyclic saturated or        partially unsaturated carbocyclic or heterocyclic ring system        containing up to 10 atoms; wherein said ring system is        optionally substituted with up to 3 substituents selected        independently from J; wherein each heteroatom in the        heterocyclic ring system is selected from the group consisting        of N, NH, O, S, SO, or SO₂;        R₁ and R₃ are each independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁ and R₃            are optionally replaced by a heteroatom selected from O, N,            NH, S, SO, or SO₂ in a chemically stable arrangement;        -   wherein each of R₁ and R₃ is independently and optionally            substituted with up to 3 substituents independently selected            from J;            R₂, R₄, and R₇ are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₂, R₄,            and R₇ are optionally replaced by a heteroatom selected from            O, N, NH, S, SO, and SO₂ in a chemically stable arrangement;        -   wherein each of R₂, R₄, and R₇ is optionally substituted            with up to 3 substituents independently selected from J;            R₅ and R_(5′) are each independently hydrogen or            (C1-C12)-aliphatic, wherein any hydrogen is optionally            replaced with halogen; wherein any terminal carbon atom of            R₅ is optionally substituted with sulfhydryl or hydroxy; or            R₅ is Ph or —CH₂Ph and R₅, is H, wherein said Ph or —CH₂Ph            group is optionally substituted with up to 3 substituents            independently selected from J; or            R₅ and R_(5′) together with the atom to which they are bound            optionally form a 3- to 6-membered saturated or partially            unsaturated ring having up to 2 heteroatoms selected from N,            NH, O, SO, and SO₂; wherein said ring is optionally            substituted with up to 2 substituents selected independently            from J;            W is:

wherein m is 0 or 1;

wherein each R₆ is independently:

-   -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein up to 3 aliphatic carbon atoms in each R₆ is optionally        replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a        chemically stable arrangement;    -   wherein R₆ is optionally substituted with up to 3 J        substituents; or    -   two R₆ groups, together with the nitrogen atom to which they are        bound, optionally form a 5- to 6-membered aromatic or a 3- to        7-membered saturated or partially unsaturated ring system having        up to 3 heteroatoms independently selected from N, NH, O, S, SO,        and SO₂, wherein said ring is optionally fused to a        (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a        (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents        selected independently from J;    -   wherein each R₈ is independently —OR′; or the R₈ groups together        with the boron atom, is a (C3-C10)-membered heterocyclic ring        having in addition to the boron up to 3 additional heteroatoms        selected from N, NR′, O, SO, and SO₂;        V is —C(O)—, —C(S)—, —S(O)—, or —S(O)₂, —;        A is hydrogen or —C(R₁₂)(R_(12′))-T-R₁₃;        T is oxygen or a bond;        R₁₂ and R_(12′) are each independently:    -   hydrogen-, or    -   (C1-C6)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₁₂ and            R_(12′) are optionally replaced by a heteroatom selected            from O, N, NH, S, SO, and SO₂ in a chemically stable            arrangement; or            R₁₂ is absent and R_(12′) is ═O;            R₁₃ is —C(O)R′, —P(O)(OR′)₂, —SO₃R′, —R′, or R₁₉;            R₁₉ is:    -   hydrogen,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein R₁₉ is optionally substituted with up to 3 J            substituents;        -   wherein up to 3 aliphatic carbon atoms in each R₁₉ are            optionally replaced by a heteroatom selected from O, NR₁₉,            S, SO, or SO₂ in a chemically stable arrangement;        -   wherein up to 3 aliphatic carbon atoms in each R₁₉ are            optionally replaced with —C(O)—;        -   wherein R₁₉ is optionally substituted with up to 3 J            substituents;        -   wherein any NR₁₉, taken together with the nitrogen and a            carbon adjacent to the nitrogen, optionally forms a 5- to            7-membered ring system, wherein said ring system optionally            contains up to three additional heteroatoms selected from O,            N, NH, S, SO, and SO₂ in a chemically stable arrangement;            R₁₄ and R₁₅ are independently halogen, —OR′, —OC(O)N(R′)₂,            —NO₂, —CN, —CF₃, —OCF₃, —R′, 1,2-methylenedioxy,            1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,            —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —C(S)R′,            —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂,            or —(CH₂)₀₋₂NHC(O)R′;            R₁₆ is R′, —C(O)R′, —P(O)(OR′)₂, or —SO₃R′;            U is O, N, or a bond;            R₁₈ and R_(18′) are optionally taken together with the            carbon atom to which they are bound to form a 5- to            7-membered saturated or partially unsaturated ring system;    -   wherein the R₁₈ and R_(18′) atoms bound to the carbon atom are        independently O or N;    -   wherein said ring optionally contains up to 1 additional        heteroatom selected from N, NH, O, S, SO, and SO₂;    -   wherein any substitutable atom is optionally singly or multiply        substituted with up to 2 substituents selected independently        from J;    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J;    -   provided that when R₁₈ and R_(18′) are optionally taken together        with the carbon atom to which they are bound to form a 5- to        7-membered saturated or partially unsaturated ring system, then        R₁₆ is R′; or        R_(18′) is ═O, ═CH₂, ═N(R′), or ═N(OR′) and R₁₈ is absent,        provided that when R₁₈ is absent and R₁₈ is ═CH₂, then U is        oxygen; and provided that when R₁₈ is absent and R_(18′) is ═O,        ═N(R′) or ═N(OR′), then U is a bond and R₁₆ is R′.

The invention also relates to processes for preparing the abovecompounds and to compositions that comprise the above compounds and theuse thereof. Such compositions may be used to pre-treat invasive devicesto be inserted into a patient, to treat biological samples, such asblood, prior to administration to a patient, and for directadministration to a patient. In each case the composition will be usedto inhibit HCV replication and to lessen the risk of or the severity ofHCV infection.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:R₉ and R_(9′) are each independently:

-   -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in each of R₉ and            R_(9′) are optionally replaced by O, N, NH, S, SO, or SO₂ in            a chemically stable arrangement;        -   wherein each of R₉ and R_(9′) is independently and            optionally substituted with up to 3 substituents            independently selected from J;        -   J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo,            thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy,            1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,            —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)₂,            —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′,            —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′,            —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂,            —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′,            —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,            —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′,            —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or            —P(O)(H)(OR′); wherein;            -   each R′ is independently selected from:            -   hydrogen-,            -   (C1-C12)-aliphatic-,            -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,            -   [(C3-C10)-cycloalkyl or                -cycloalkenyl]-(C1-C12)-aliphatic-,            -   (C6-C10)-aryl-,            -   (C6-C10)-aryl-(C1-C12)aliphatic-,            -   (C3-C10)-heterocyclyl-,            -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,            -   (C5-C10)-heteroaryl-, and            -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;            -   wherein up to 5 atoms in R′ are optionally and                independently substituted with J;            -   wherein two R′ groups bound to the same atom optionally                form a 5- to 6-membered aromatic or a 3- to 7-membered                saturated or partially unsaturated ring system having up                to 3 heteroatoms independently selected from N, NH, O,                S, SO, and SO₂, wherein said ring is optionally fused to                a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl,                or a (C3-C10)heterocyclyl, wherein any ring has up to 3                substituents selected independently from J;                R₁₀, R_(10′), R₁₁, and R_(11′) are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein any ring is optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein up to 3 aliphatic carbon atoms in each of R₁₀,            R_(10′), R₁₁, and R_(11′) are optionally replaced by a            heteroatom selected from O, NH, S, SO, or SO₂ in a            chemically stable arrangement;        -   wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is            independently and optionally substituted with up to 3            substituents independently selected from J; or            R₁₀ is —OR′ and R_(10′), is H; or            R₁₀ and R_(10′) are both —OR′ or —SR′; or            R₁₀ and R_(10′) are both fluorine; or            R₁₀ and R_(10′) are optionally taken together with the            carbon atom to which they are bound to form a 5- to            7-membered saturated or partially unsaturated ring system;    -   wherein the R₁₀ and R_(10′) atoms bound to the carbon atom are        independently C(H), N, NH, O, S, SO, or SO₂;    -   wherein said ring optionally contains up to 4 heteroatoms        independently selected from N, NH, O, S, SO, and SO₂;    -   wherein any atom is optionally singly or multiply substituted        with up to 2 substituents selected independently from J; and    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J; or        R₉ and R₁₀ are optionally taken together with the ring atoms to        which they are bound to form a 5- to 6-membered aromatic or a 3-        to 7-membered saturated or partially unsaturated ring system up        to 3 heteroatoms independently selected from N, NH, O, S, SO, or        SO₂; wherein said ring system is optionally substituted with up        to 3 substituents selected independently from J; or        R₁₀ and R₁₁ are optionally taken together with the ring atoms to        which they are bound to form a 5- to 6-membered aromatic or a 3-        to 7-membered saturated or partially unsaturated ring system        having up to 3 heteroatoms independently selected from N, NH, O,        S, SO, or SO₂; wherein said ring is optionally substituted with        up to 3 substituents selected independently from J; or        R₉ and R₁₁ are optionally taken together with the ring atoms to        which they are bound to form a bridged bicyclic saturated or        partially unsaturated carbocyclic or heterocyclic ring system        containing up to 10 atoms; wherein said ring system is        optionally substituted with up to 3 substituents selected        independently from J; wherein each heteroatom in the        heterocyclic ring system is selected from the group consisting        of N, NH, O, S, SO, or SO₂;        R₁ and R₃ are each independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁ and R₃            are optionally replaced by a heteroatom selected from O, N,            NH, S, SO, or SO₂ in a chemically stable arrangement;        -   wherein each of R₁ and R₃ is independently and optionally            substituted with up to 3 substituents independently selected            from J;            R₂, R₄, and R₇ are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₂, R₄,            and R₇ are optionally replaced by a heteroatom selected from            O, N, NH, S, SO, and SO₂ in a chemically stable arrangement;        -   wherein each of R₂, R₄, and R₇ is optionally substituted            with up to 3 substituents independently selected from J;            R₅ and R_(5′) are each independently hydrogen or            (C1-C12)-aliphatic, wherein any hydrogen is optionally            replaced with halogen; wherein any terminal carbon atom of            R₅ is optionally substituted with sulfhydryl or hydroxy; or            R₅ is Ph or —CH₂Ph and R_(5′) is H, wherein said Ph or            —CH₂Ph group is optionally substituted with up to 3            substituents independently selected from J; or            R₅ and R_(5′) together with the atom to which they are bound            optionally form a 3- to 6-membered saturated or partially            unsaturated ring having up to 2 heteroatoms selected from N,            NH, O, SO, and SO₂; wherein said ring is optionally            substituted with up to 2 substituents selected independently            from J;            W is:

-   -   wherein m is 0 or 1;    -   wherein each R₆ is independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each R₆ is            optionally replaced by a heteroatom selected from O, NH, S,            SO, or SO₂ in a chemically stable arrangement;        -   wherein R₆ is optionally substituted with up to 3 J            substituents; or        -   two R₆ groups, together with the nitrogen atom to which they            are bound, optionally form a 5- to 6-membered aromatic or a            3- to 7-membered saturated or partially unsaturated ring            system having up to 3 heteroatoms independently selected            from N, NH, O, S, SO, and SO₂, wherein said ring is            optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,            (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any            ring has up to 3 substituents selected independently from J;        -   wherein each R₈ is independently —OR′; or the R₈ groups            together with the boron atom, is a (C3-C10)-membered            heterocyclic ring having in addition to the boron up to 3            additional heteroatoms selected from N, NR′, O, SO, and SO₂;            V is —C(O)—, —C(S)—, —S(O)—, or —S(O)₂, —;            A is hydrogen or —C(R₁₂)(R_(12′))-T-R₁₃;            T is oxygen or a bond;            R₁₂ and R_(12′) are each independently:    -   hydrogen-, or    -   (C1-C6)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₁₂ and            R_(12′) are optionally replaced by a heteroatom selected            from O, N, NH, S, SO, and SO₂ in a chemically stable            arrangement; or            R₁₂ is absent and R_(12′) is ═O;            R₁₃ is —C(O)R′, —P(O)(OR′)₂, —SO₃R′, —R′, or —R₁₉;            R₁₉ is:    -   hydrogen,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each R₁₉ are            optionally replaced by a heteroatom selected from O, NR₁₉,            S, SO, or SO₂ in a chemically stable arrangement;        -   wherein up to 3 aliphatic carbon atoms in each R₁₉ are            optionally replaced with —C(O)—;        -   wherein R₁₉ is optionally substituted with up to 3 J            substituents;        -   wherein any NR₁₉, taken together with the nitrogen and a            carbon adjacent to the nitrogen, optionally forms a 5- to            7-membered ring system, wherein said ring system optionally            contains up to three additional heteroatoms selected from O,            N, NH, S, SO, and SO₂ in a chemically stable arrangement;            R₁₄ and R₁₅ are independently halogen, —OR′, —OC(O)N(R′)₂,            —NO₂, —CN, —CF₃, —OCF₃, —R′, 1,2-methylenedioxy,            1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,            —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —C(S)R′,            —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂,            or —(CH₂)₀₋₂NHC(O)R′;            R₁₆ is R′, —C(O)R′, —P(O)(OR′)₂, or —SO₃R′;            U is O, N, or a bond; and            R₁₈ and R_(18′) are optionally taken together with the            carbon atom to which they are bound to form a 5- to            7-membered saturated or partially unsaturated ring system;    -   wherein the R₁₈ and R_(18′) atoms bound to the carbon atom are        independently O or N;    -   wherein said ring optionally contains up to 1 additional        heteroatom selected from N, NH, O, S, SO, and SO₂;    -   wherein any substitutable atom is optionally singly or multiply        substituted with up to 2 substituents selected independently        from J;    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J;    -   provided that when R₁₈ and R_(18′) are optionally taken together        with the carbon atom to which they are bound to form a 5- to        7-membered saturated or partially unsaturated ring system, then        R₁₆ is R′; or        R_(18′) is ═O, ═CH₂, ═N(R′), or ═N(OR′) and R₁₈ is absent,        provided that when R₁₈ is absent and R_(18′) is ═CH₂, then U is        oxygen; and    -   provided that when R₁₈ is absent and R_(18′) is ═O, ═N(R′) or        ═N(OR′), then U is a bond and R₁₆ is R′.

Definitions

The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system. Phenyl is an example of a monocyclicaromatic ring system. Bicyclic aromatic ring systems include systemswherein both rings are aromatic, e.g., naphthyl, and systems whereinonly one of the two rings is aromatic, e.g., tetralin. It is understoodthat as used herein, the term “(C6-C10)-aryl-” includes any one of a C6,C7, C8, C9, and C10 monocyclic or bicyclic carbocyclic aromatic ring.

The term “heterocyclyl” as used herein means a monocyclic or bicyclicnon-aromatic ring system having 1 to 3 heteroatom or heteroatom groupsin each ring selected from O, N, NH, S, SO, and SO₂ in a chemicallystable arrangement. In a bicyclic non-aromatic ring system embodiment of“heterocyclyl” one or both rings may contain said heteroatom orheteroatom groups. It is understood that as used herein, the term“(C5-C10)-heterocyclyl-” includes any one of a C5, C6, C7, C8, C9, andC10 monocyclic or bicyclic non-aromatic ring system having 1 to 3heteroatom or heteroatom groups in each ring selected from O, N, NH, andS in a chemically stable arrangement.

The term “heteroaryl” as used herein means a monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH, and S in a chemically stablearrangement. In such a bicyclic aromatic ring system embodiment of“heteroaryl”:

one or both rings may be aromatic; and

one or both rings may contain said heteroatom or heteroatom groups. Itis understood that as used herein, the term “(C5-C10)-heteroaryl-”includes any one of a C5, C6, C7, C8, C9, and C10 monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH, and S in a chemically stablearrangement.

The term “aliphatic” as used herein means a straight chained or branchedalkyl, alkenyl or alkynyl. It is understood that as used herein, theterm “(C1-C12)-aliphatic-” includes any one of a C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, and C12 straight or branched alkyl chain of carbonatoms. It is also understood that alkenyl or alkynyl embodiments need atleast two carbon atoms in the aliphatic chain. The term “cycloalkyl orcycloalkenyl” refers to a monocyclic or fused or bridged bicycliccarbocyclic ring system that is not aromatic. Cycloalkenyl rings haveone or more units of unsaturation. It is also understood that as usedherein, the term “(C3-C10)-cycloalkyl- or -cycloalkenyl-” includes anyone of a C3, C4, C5, C6, C7, C8, C9, and C10 monocyclic or fused orbridged bicyclic carbocyclic ring. Preferred cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, nornbornyl, adamantyl and decalin-yl.

The phrase “chemically stable arrangement” as used herein refers to acompound structure that renders the compound sufficiently stable toallow manufacture and administration to a mammal by methods known in theart. Typically, such compounds are stable at a temperature of 40° C. orless, in the absence of moisture or other chemically reactive condition,for at least a week.

Preferred Embodiments

According to an embodiment of compounds of formula I, V is —C(O)—.

According to another embodiment, the present invention provides acompound of formula IA:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),R₁₄, R₁₅, R₁₆, R₁₈, R_(18′), A, U, and W are as defined in any of theembodiments herein.

According to another embodiment of compounds of formula I,

A is —C(R₁₂)(R_(12′))-T-R₁₃;

R₁₂ and R_(12′) are both hydrogen;

T is oxygen;

R₁₃ is —C(O)R′, —P(O)(OR′)₂, —SO₃R′, or —R′;

R₁₄ and R₁₅ are both —R′;

R_(18′) is ═O and R₁₈ is absent;

U is a bond; and

R₁₆ is R′, wherein R′ is selected from:

-   -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-;        -   wherein up to 5 atoms in R′ are optionally and independently            substituted with J.

According to another embodiment of compounds of formula I,

R₁₃ is —C(O)R′, —P(O)(OR′)₂, or —R′;

R₁₄ and R₁₅ are both —R′ and R′ is (C1-C12)-aliphatic-; and

R₁₆ is R′, wherein R′ is (C1-C12)-aliphatic-.

According to another embodiment, the present invention provides acompound of formula IB:

wherein:

R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R₁₃, and W are as defined in any of the embodiments herein.

According to an embodiment of compounds of formula IB, R₁₆ is —R′wherein R′ is preferably methyl; R₁₄ and R₁₅ are both —R′ and R′ ispreferably methyl; R₁₃ is —C(O)R′ or —P(O)(OR′)₂, wherein R′ is asdefined in any of the embodiments herein; and R₁, R₂, R₃, R₄, R₅,R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and W are as definedin any of the embodiments herein.

According to another embodiment of compounds of formula I,

A is —C(R₁₂)(R_(12′))-T-R₁₃;

R₁₂ is hydrogen and R_(12′) is (C1-C6)-aliphatic-;

-   -   wherein up to two aliphatic carbon atoms in R_(12′) are        optionally replaced by a heteroatom selected from O, N, NH, S,        SO, and SO₂ in a chemically stable arrangement;        T is oxygen;        R₁₃ is —C(O)R′, —P(O)(OR′)₂, —SO₃R′, or —R′;        R₁₄ and R₁₅ are both —R′;        R_(18′), is ═O and R₁₈ is absent;        U is a bond; and        R₁₆ is R′, wherein R′ is selected from:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-;        -   wherein up to 5 atoms in R′ are optionally and independently            substituted with J.

According to another embodiment of compounds of formula I,

R_(12′) is (C1-C6)-aliphatic-;

R₁₃ is —C(O)R′, —P(O)(OR′)₂, or —R′;

R₁₄ and R₁₅ are both —R′ and R′ is (C1-C12)-aliphatic-;

R₁₆ is R′, wherein R′ is (C1-C12)-aliphatic-.

According to another embodiment, the present invention provides acompound of formula IC:

wherein:

R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R_(12′), R₁₃, and W are as defined in any of the embodimentsherein.

According to an embodiment of compounds of formula IC, R₁₆ is —R′wherein R′ is preferably methyl; R₁₄ and R₁₅ are both —R′ and R′ ispreferably methyl; R₁₃ is —C(O)R′ or —P(O)(OR′)₂, wherein R′ is asdefined in any of the embodiments herein; R_(12′) is methyl and R₁, R₂,R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and Ware as defined in any of the embodiments herein.

According to another embodiment of compounds of formula I,

A is —C(R₁₂)(R_(12′))-T-R₁₃;

R₁₂ is absent and R_(12′) is ═O;

T is oxygen or a bond;

R₁₃ is —R₁₉;

R₁₄ and R₁₅ are both —R′;

R_(18′) is ═O and R₁₈ is absent;

U is a bond; and

R₁₆ is R′, wherein R′ is selected from:

-   -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-;    -   wherein up to 5 atoms in R′ are optionally and independently        substituted with J.

According to another embodiment, the present invention provides acompound of formula ID:

wherein:

R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R_(12′), R₁₉, T, and W are as defined in any of the embodimentsherein.

According to an embodiment of compounds of formula ID, R₁, R₂, R₃, R₄,R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and W are asdefined in any of the embodiments herein;

T is a bond;

R₁₆ is —R′ wherein R′ is preferably methyl;

R₁₄ and R₁₅ are both —R′ and R′ is preferably methyl;

R₁₃ is R₁₉, wherein R₁₉ is as defined in any of the embodiments herein.

According to another embodiment of compounds of formula ID, R₁₉ is:

-   -   (C1-C12)-aliphatic-,        -   wherein 1 to 2 aliphatic carbon atoms in each R₁₉ are            optionally replaced by a heteroatom selected from O or NR₁₉,            in a chemically stable arrangement;        -   wherein 1 to 2 aliphatic carbon atoms in each R₁₉ is            optionally replaced with —C(O)—;        -   wherein R₁₉ is optionally substituted with up to 3 J            substituents.

According to a preferred embodiment of compounds of formula ID, R₁₉ is:

-   -   (C3-C6)-aliphatic-,    -   wherein 1 to 2 aliphatic carbon atoms in each R₁₉ are optionally        replaced by a heteroatom selected from O or NR₁₉, in a        chemically stable arrangement;    -   wherein 1 to 2 aliphatic carbon atoms in each R₁₉ is optionally        replaced with —C(O)—;    -   wherein R₁₉ is optionally substituted with up to 3 J        substituents.

According to another embodiment of compounds of formula I,

R_(18′), is ═CH₂, and R₁₈ is absent;

U is oxygen;

R₁₆ is R′, —C(O)R′, —P(O)(OR′)₂, or —SO₃R′;

R₁₄ and R₁₅ are both —R′; and

A is hydrogen.

According to another embodiment of compounds of formula I,

R₁₆ is R′, —C(O)R′, or —P(O)(OR′)₂;

R₁₄ and R₁₅ are both —R′ and R′ is (C1-C12)-aliphatic-.

According to another embodiment, the present invention provides acompound of formula IE:

wherein:

R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R₁₆, and W are as defined in any of the embodiments herein.

According to an embodiment of compounds of formula IE, R₁₆ is —C(O)R′,—P(O)(OR′)₂,; R₁₄ and R₁₅ are both —R′ and R′ is preferably methyl; A ishydrogen; and R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′),R₁₁, R_(11′), and W are as defined in any of the embodiments herein.

According to an embodiment of compounds of formula I,

R_(18′) is ═N(R′) or ═N(OR′) and R₁₈ is absent;

U is a bond;

R₁₆ is R′;

R₁₄ and R₁₅ are both —R′; and

A is hydrogen.

In another embodiment of compounds of formula I, U is —NR′—.

According to another embodiment of compounds of formula I, R₁₄ and R₁₅are both —R′ and R′ is (C1-C12)-aliphatic-.

According to another embodiment, the present invention provides acompound of formula IF:

wherein:

R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R₁₆, R_(18′), and W are as defined in any of the embodimentsherein.

According to an embodiment of compounds of formula IF, R_(18′) is ═N(R′)or ═N(OR′) and R₁₈ is absent; R₁₆ is R′; R₁₄ and R₁₅ are both —R′ and R′is preferably methyl; A is hydrogen; and R₁, R₂, R₃, R₄, R₅, R_(5′), R₇,R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and W are as defined in any ofthe embodiments herein.

According to another embodiment of compounds of formula I,

R₁₈ and R_(18′) are optionally taken together with the carbon atom towhich they are bound to form a 5- to 7-membered saturated or partiallyunsaturated ring system;

-   -   wherein the R₁₈ and R_(18′) atoms bound to the carbon atom are        independently O or N;    -   wherein said ring optionally contains up to 1 additional        heteroatom selected from N, NH, O, S, SO, and SO₂;    -   wherein any substitutable atom is optionally singly or multiply        substituted with up to 2 substituents selected independently        from J;    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J;        U is a bond;        R₁₆ is R′;        R₁₄ and R₁₅ are both —R′; and        A is hydrogen.

According to another embodiment of compounds of formula I,

the R₁₈ and R_(18′) atoms bound to the carbon atom are 0 and the ringformed when R₁₈ and R_(18′) are optionally taken together with thecarbon atom to which they are bound optionally contains up to 1additional oxygen atom and is optionally substituted with up to 2 Jsubstituents.

According to another embodiment, the present invention provides acompound of formula IG:

wherein:

r is 0, 1, or 2, R₁₆ is R′, R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉,R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and W are as defined in any of theembodiments herein.

According to an embodiment of compounds of formula IG, the R₁₈ andR_(18′) atoms bound to the carbon atom are O; the ring formed when R₁₈and R_(18′) are optionally taken together with the carbon atom to whichthey are bound is a 5- or 6-membered ring system optionally substitutedwith up to 2 J substituents; R₁₆ is R′; R₁₄ and R₁₅ are both —R′ and R′is preferably methyl; A is hydrogen; and R₁, R₂, R₃, R₄, R₅, R_(5′), R₇,R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and W are as defined in any ofthe embodiments herein.

According to another embodiment, this invention does not includecompounds wherein T is 3-acetyl-4,5-dimethyl-1H-pyrrole (e.g., seecompounds 63-64 at page 95, and compounds 66-67 at page 96 of WO03/087092).

According to another embodiment, this invention does not includecompounds wherein:

V is —C(O)—, —C(S)—, —S(O)—, or —S(O)₂, —; and

radical T is:

wherein:

R₂₀ is —H, —S(O)R^(O), —S(O)₂R^(O), —C(O)R^(O), —C(O)OR^(O),—C(O)N(R^(O))₂, —N(R^(O))C(O)R^(O), —N(COR^(O))COR^(O), —SO₂N(R^(O))₂,—SO₃R^(O), —C(O)C(O)R^(O), —C(O)CH₂C(O)R^(O), —C(S)R^(O),—C(S)N(R^(O))₂, —(CH₂)₀₋₂NHC(O)R^(O), —N(R^(O))N(R^(O))COR^(O),—N(R^(O))N(R^(O))C(O)OR^(O), —N(R^(O))N(R^(O))CON(R^(O))₂,—N(R^(O))SO₂R^(O), —N(R^(O))SO₂N(R^(O))₂, —N(R^(O))C(O)OR^(O),—N(R^(O))C(O)R^(O), —N(R^(O))C(S)R^(O), —N(R^(O))C(O)N(R^(O))₂,—N(R^(O))C(S)N(R^(O))₂, —N(COR^(O))COR^(O), —N(OR^(O))R^(O),—C(═NH)N(R^(O))₂, —C(O)N(OR^(O))R^(O), —C(═NOR^(O))R^(O),—OP(O)(OR^(O))₂, —P(O)(R^(O))₂, —P(O)(OR^(O))₂, or —P(O)(H)(OR^(O));

R₂₁ and R₂₂ are independently halogen, —OR^(O), —OC(O)N(R^(O))₂, —NO₂,—CN, —CF₃, —OCF₃, —R^(O), oxo, 1,2-methylenedioxy, 1,2-ethylenedioxy,—N(R^(O))₂, —SRO, —SOR^(O), —SO₂R^(O), —SO₂N(R^(O))₂, —SO₃R^(O),—C(O)R^(O), —C(O)C(O)R^(O), —C(O)CH₂C(O)R^(O), —C(S)R^(O), —C(O)OR^(O),—OC(O)R^(O), —C(O)N(R^(O))₂, —OC(O)N(R^(O))₂, —C(S)N(R^(O))₂,—(CH₂)₀₋₂NHC(O)R^(O);

Z₂ is ═O, ═NR^(O), ═NOR^(O), or ═CH₂;

R₂₃ is —OR^(O), —CF₃, —OCF₃, —R^(O), —N(R^(O))₂, —C(O)R^(O), or—N(R^(O)) COR^(O);

two R^(O) groups together with the atoms to which they are bound form a3- to 10-membered aromatic or non-aromatic ring having up to 3heteroatoms independently selected from N, NH, O, S, SO, or SO₂, whereinthe ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring hasup to 3 substituents selected independently from J₃; or

each R^(O) is independently selected from:

-   -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C6-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        wherein R^(O) has up to 3 substituents selected independently        from J₃; and

J₃ is halogen, —OR^(O), —OC(O)N(R^(O))₂, —NO₂, —CN, —CF₃, —OCF₃, —R^(O),oxo, thioxo, 1,2-methylenedioxy, —N(R^(O))₂, —SR^(O), —SOR^(O),—SO₂R^(O), —SO₂N(R^(O))₂, —SO₃R^(O), —C(O)R^(O), —C(O)C(O)R^(O),—C(O)CH₂C(O)R^(O), —C(S)R^(O), —C(O)OR^(O), —OC(O)R^(O), —C(O)N(R^(O))₂,—OC(O)N(R^(O))₂, —C(S)N(R^(O))₂, —(CH₂)₀₋₂NHC(O)R^(O),—N(R^(O))N(R^(O))COR^(O), —N(R^(O))N(R^(O))C(O)OR^(O),—N(R^(O))N(R^(O))CON(R₂, —N(R^(O))SO₂R^(O), —N(R^(O))SO₂N(R^(O))₂,—N(R^(O))C(O)OR^(O), —N(R^(O))C(O)R^(O), —N(R^(O))C(S)R^(O),—N(R^(O))C(O)N(R^(O))₂, —N(R^(O))C(S)N(R^(O))₂, —N(COR^(O))COR^(O),—N(OR^(O))R^(O), —CN, —C(═NH)N(R^(O))₂, —C(O)N(OR^(O))R^(O),—C(═NOR^(O))R^(O), —OP(O)(OR^(O))₂, —P(O)(R^(O))₂, —P(O)(OR^(O))₂, or—P(O)(H)(OR^(O))(e.g., see compounds of formula II at page 22 of WO03/087092).

According to another embodiment of compounds of formula I, when R_(18′)is ═O, R₁₈ is absent, U is a bond, and R₁₆ is R′, then A is—C(R₁₂)(R_(12′))-T-R₁₃.

According to another embodiment of compounds of formula I, when A ishydrogen, R₁₆ is R′, —C(O)R′, —P(O)(OR′)₂, or —SO₃R′;

U is O, or N, or a bond; and

R₁₈ and R_(18′) are optionally taken together with the carbon atom towhich they are bound to form a 5- to 7-membered saturated or partiallyunsaturated ring system;

-   -   wherein the R₁₈ and R_(18′) atoms bound to the carbon atom are        independently O or N;    -   wherein said ring optionally contains up to 1 additional        heteroatom selected from N, NH, O, S, SO, and SO₂;    -   wherein any substitutable atom is optionally singly or multiply        substituted with up to 2 substituents selected independently        from J;    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J;    -   provided that when R₁₈ and R_(18′) are optionally taken together        with the carbon atom to which they are bound to form a 5- to        7-membered saturated or partially unsaturated ring system, then        R₁₆ is R′; or        R_(18′) is ═O, ═CH₂, ═N(R′), or ═N(OR′) and R₁₈ is absent,        provided that when R₁₈ is absent and R_(18′) is ═CH₂, then U is        oxygen; and    -   provided that when R₁₈ is absent and R_(18′) is ═O, ═N(R′) or        ═N(OR′), then U is a bond and R₁₆ is R′.

According to another embodiment of compounds of formula I, the

radical is:

wherein:

n is 0, 1, or 2;

Z and Z′ are independently C(H), N, NH, O, or S;

R₉, R_(9′), R₁₁, and R_(11′), are as defined in any of the embodimentsherein; and

the spirocyclic ring containing Z and Z′ is optionally substituted withup to 3 J substituents, wherein J is as defined in any of theembodiments herein.

According to another embodiment the

radical is:

wherein:

R₁₁ and R_(11′) are both H;

n is 0, 1, or 2;

R₉ and R_(9′) are as defined in any of the embodiments herein; and

the spirocyclic ring containing Z and Z′ is optionally substituted withup to 3 J substituents, wherein J is as defined in any of theembodiments herein.

According to a preferred embodiment, the

radical is:

wherein:

n is 0 or 1.

According to another embodiment, the present invention provides acompound of formula IH:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆,R₁₈, R_(18′), n, V, A, U, Z, Z′ and W are as defined in any of theembodiments herein.

According to another embodiment the

radical is:

wherein:

Z and Z′ are independently C(H), N, NH, O, or S;

R₉, R_(9′), R₁₁, and R_(11′) are as defined in any of the embodimentsherein; and

the fused benzo ring is optionally substituted with up to 3 Jsubstituents, wherein J is as defined in any of the embodiments herein.

According to another embodiment, the present invention provides acompound of formula IJ:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆,R₁₈, R_(18′), V, A, U, Z, Z′ and W are as defined in any of theembodiments herein; and

the fused benzo ring is optionally substituted with up to 3 Jsubstituents, wherein J is as defined in any of the embodiments herein.

According to a preferred embodiment for compounds of formula IJ, Z andZ′ are S, R₉ and R_(9′) are H, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₁₁,R_(11′), R₁₄, R₁₅, R₁₆, R₁₈, R_(18′)V, A, U, and W are as defined in anyof the embodiments herein and the fused benzo ring is optionallysubstituted with up to 3 J substituents, wherein J is as defined in anyof the embodiments herein.

According to another embodiment of compounds of formula I, the

radical is:

wherein:

R₉, R_(9′), R₁₁, and R_(11′) are H.

In a preferred embodiment, the

radical is:

wherein:R₉, R_(9′), R₁₁, and R_(11′) are H.

According to another embodiment, the present invention provides acompound of formula IK:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆,R₁₈, R_(18′), V, A, U, and W are as defined in any of the embodimentsherein.

According to another embodiment of compounds of formula I, in the

radical

-   -   R₉, R₁₀, R_(10′), R₁₁, and R_(11′) are H; and    -   R_(9′) is:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-;    -   wherein up to three aliphatic carbon atoms in R_(9′) may be        replaced by O, N, NH, S, SO, or SO₂;    -   wherein R_(9′) is independently and optionally substituted with        up to 3 substituents independently selected from J.

According to another embodiment of compounds of formula I, the

radical is:

According to another embodiment of compounds of formula I, in the

radical

-   -   R₉, R_(9′), R₁₀, R₁₁, and R_(11′) are H; and    -   R_(10′) is:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   (C6-C10)-aryl-,    -   wherein any ring is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;    -   wherein up to 3 aliphatic carbon atoms in R_(10′) may be        replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a        chemically stable arrangement;    -   wherein R_(10′), is independently and optionally substituted        with up to 3 substituents independently selected from J.

According to another embodiment of compounds of formula I, the

radical is:

According to yet another embodiment of compounds of formula I, in the

radical

-   -   R₉, R_(9′), R₁₀, R_(10′), and R₁₁ are H; and    -   R_(11′) is:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   (C6-C10)-aryl-,        -   wherein any ring is optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein up to 3 aliphatic carbon atoms in R_(11′) may be            replaced by a heteroatom selected from O, NH, S, SO, or SO₂            in a chemically stable arrangement;        -   wherein R_(11′), is independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment of compounds of formula I, the

radical is:

According to another embodiment of compounds of formula I, in the

radical

-   -   R₉, R₁₀, R₁₁, and R_(11′) are H; and    -   R_(9′) and R_(10′) are:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   wherein up to 3 aliphatic carbon atoms in R_(9′), and R_(10′),        may be replaced by a heteroatom selected from O, NH, S, SO, or        SO₂ in a chemically stable arrangement;    -   wherein R_(9′) and R_(10′) are independently and optionally        substituted with up to 3 substituents independently selected        from J.

According to another embodiment of compounds of formula I, the

radical is:

According to another embodiment of compounds of formula I, in the

radical

-   -   R₉, R_(9′), R_(10′), R₁₁, and R_(11′) are H; and    -   R′ is selected from:    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein up to 5 atoms in R′ are optionally and independently        substituted with J.

According to another embodiment of compounds of formula I, the

radical is:

wherein up to 5 atoms in R′ are optionally and independently substitutedwith J.

According to another embodiment of compounds of formula I, the

radical is:

wherein up to 5 atoms in R′ are optionally and independently substitutedwith J.

According to yet another embodiment of compounds of formula I, in the

radical

-   -   R₉, R_(9′), R_(10′), R₁₁, and R_(11′) are H; and    -   R′ is selected from:    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 5 atoms in R′ are optionally and independently            substituted with J.

According to a preferred embodiment of compounds of formula I, the

radical is:

wherein up to 5 atoms in R′ are optionally and independently substitutedwith J.

According to another embodiment, the present invention provides acompound of formula IL:

wherein:

R′, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₄, R₁₅,R₁₆, R₁₈, R_(18′), V, A, U, and W are as defined in any of theembodiments herein.

According to another embodiment of compounds of formula I, the

radical is:

wherein;

ring A is a 5- to 6-membered aromatic or a 3- to 7-membered non-aromaticring system having up to 3 heteroatoms independently selected from N,NH, O, SO, or SO₂;

wherein said ring A is optionally fused to a (C6-C10)aryl,(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;

wherein any ring has up to 3 substituents selected independently from J;and

R₉, R_(9′), R_(10′), and R_(11′) are as defined in any of theembodiments herein.

According to another embodiment of compounds of formula I, the

radical is:

According to another embodiment of compounds of formula I, the

radical is:

According to another embodiment of compounds of formula I, the

radical is:

According to a preferred embodiment, the

radical is:

According to another embodiment, the present invention provides acompound of formula IM:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R_(10′), R_(11′), R₁₄, R₁₅,R₁₆, R₁₈, R_(18′), V, A, U, W, and ring A are as defined in any of theembodiments herein.

According to another embodiment of compounds of formula I, the

radical is:

wherein;

ring A is a 5- to 6-membered aromatic or a 3- to 7-membered non-aromaticring system having up to 3 heteroatoms independently selected from N,NH, O, SO, or SO₂;

wherein said ring A is optionally fused to a (C6-C10)aryl,(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;

wherein any ring has up to 3 substituents selected independently from J;and

R_(9′), R_(10′), R₁₁, and R_(11′) are as defined in any of theembodiments herein.

According to another embodiment of compounds of formula I, the

radical is:

According to yet another embodiment of compounds of formula I, the

radical is:

According to another embodiment, the present invention provides acompound of formula IN:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R_(9′), R_(10′), R_(11′), R₁₁, R₁₄, R₁₅,R₁₆, R₁₈, R_(18′), V, A, U, W, and ring A are as defined in any of theembodiments herein.

According to another embodiment of compounds of formula I, the

radical is:

wherein:

ring B forms a 3- to a 20-membered carbocyclic or heterocyclic ringsystem;

wherein each ring B is either aromatic or nonaromatic;

wherein each heteroatom in the heterocyclic ring system is N, NH, O, SO,or SO₂;

wherein ring B is optionally fused to a (C6-C10)aryl,(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;

wherein each ring has up to 3 substituents selected independently fromJ; and

R_(9′) and R_(11′) are as defined in any of the embodiments herein.

According to another embodiment, the

radical is:

According to yet another embodiment, the present invention provides acompound of formula IO:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R_(9′), R_(11′), R₁₄, R₁₅, R₁₆, R₁₈,R_(18′), V, A, U, W, and ring B are as defined in any of the embodimentsherein.

According to another embodiment, W in compounds of formula I is:

wherein in the W, the NR₆R₆ is selected from —NH—(C1-C6 aliphatic), —NH—(C3-C6 cycloalkyl), —NH—CH(CH₃)-aryl, or —NH—CH(CH₃)-heteroaryl, whereinsaid aryl or said heteroaryl is optionally substituted with up to 3halogens.

According to another embodiment in compounds of formula I, the NR₆R₆ inthe W radical is:

According to another embodiment in compounds of formula I, the NR₆R₆ inthe W radical is:

More preferably, in the W, the NR₆R₆ is:

Even more preferably, in the W, the NR₆R₆ is:

According to another embodiment in compounds of formula I, the NR₆R₆ inthe W radical is:

According to another embodiment in compounds of formula I, the NR₆R₆ inthe W radical is:

In yet another embodiment, in the W, the NR₆R₆ is:

According to another embodiment, the present invention provides acompound of formula IP:

wherein:

R₁, R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R₁₄, R₁₅, R₁₆, R₁₈, R_(18′), V, A, and U are as defined in anyof the embodiments herein.

According to another embodiment W in compounds of formula I is:

wherein R₈ is as defined above.

According to another embodiment for W in compounds of formula I, each R₈together with the boron atom, is a (C5-C10)-membered heterocyclic ringhaving no additional heteroatoms other than the boron and the two oxygenatoms. Preferred groups are selected from:

wherein R′ is, preferably, (C1-C6)-aliphatic and is, more preferably,methyl.

According to another embodiment in compounds of formula I, R_(5′) ishydrogen and R₅ is:

According to a preferred embodiment in compounds of formula I, R_(5′) ishydrogen and R₅ is:

According to another embodiment, the present invention provides acompound of formula IQ:

wherein:

R₁, R₂, R₃, R₄, R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₄,R₁₅, R₁₆, R₁₈, R_(18′), V, A, and U are as defined in any of theembodiments herein.

According to a preferred embodiment for compounds of formula IQ, R₁, R₂,R₃, R₄, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆, R₁₈,R_(18′), V, A, and U are as defined in any of the embodiments herein,and NR₆R₆ is:

According to another embodiment in compounds of formula I, R_(5′) and R₅is:

According to another embodiment for compounds of formula I, R₂, R₄, andR₇, are each independently H, methyl, ethyl, or propyl.

According to a preferred embodiment R₂, R₄, and R₇ are each H.

According to another embodiment, the present invention provides acompound of formula IR:

wherein:

R₁, R₂, R₃, R₄, R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₄,R₁₅, R₁₆, R₁₈, R_(18′), V, A, and U are as defined in any of theembodiments herein.

According to a preferred embodiment for compounds of formula IR, R₁, R₂,R₃, R₄, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆, R₁₈,R_(18′), V, A, and U are as defined in any of the embodiments herein,and NR₆R₆ is:

According to another embodiment in compounds of formula I, R₃ is:

According to a preferred embodiment in compounds of formula I, R₃ is:

According to a more preferred embodiment in compounds of formula I, R₃is:

According to another embodiment, the present invention provides acompound of formula IS:

wherein:

R₁, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆, R₁₈,R_(18′), V, A, and U are as defined in any of the embodiments herein.

According to another embodiment in compounds of formula I, R₁ is:

According to a preferred embodiment in compounds of formula I, R₁ is:

More preferably, R₁ is cyclohexyl.

According to another embodiment, the present invention provides acompound of formula IT:

wherein:

R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₄, R₁₅, R₁₆, R₁₈, R_(18′),V, A, and U are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IT, R₆, R₉,R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and R₁₂ are as defined in any of theembodiments herein, and NR₆R₆ is:

According to another embodiment for compounds of formulae I, and IA-IT,R₁₄ and R₁₅ are both —R′ and R′ is -(C1-C6 aliphatic). More preferably,R₁₄ and R₁₅ are both methyl.

The compounds of this invention may contain one or more asymmetriccarbon atoms and thus may occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomeric forms of these compounds are expresslyincluded in the present invention. Each stereogenic carbon may be of theR or S configuration.

Preferably, the compounds of this invention have the structure andstereochemistry depicted in formulae IA-IT.

Any of the preferred embodiments recited herein, including thoseembodiments in the above species, may define formula I individually orbe combined to produce a preferred embodiment of this invention.

The compounds of this invention contain, and may be modified to contain,appropriate functionalities to enhance selective biological propertiescompared to the corresponding parent compound. Such modifications areknown in the art and include those which increase biological penetrationinto a given biological compartment (e.g., blood, lymphatic system,central nervous system), increase oral availability, increase solubilityto allow administration by injection, alter metabolism and alter rate ofexcretion.

Without being bound by theory, we believe the compounds of thisinvention may enhance biological properties by behaving as prodrugs.

Chemical modifications of a drug into a bio- or chemically-reversibleprodrug can confer temporary aqueous solubility to the drug substancethat allows absorption following oral administration. See generally,Liu, S.; Han, C.; Wang, B. “Prodrug Derivatization as a Means to Enhancethe Delivery of Peptide and Peptidomimetic Drugs” in Frontiers ofBiotechnology and Pharmaceuticals, Ming Guo, ed, Science Press, NewYork, pp. 291-310 (2002) and Borchardt, R. T. and Wang, B. “ProdrugStrategies to Improve the Oral Absorption of Peptides and PeptideMimetics” in Controlled Drug Delivery. Designing Technologies for theFuture. Park. K. and Mrsny, R. J. Eds, American Chemical Society,Washington, D.C., pp. 36-45 (2000)

Prodrug strategies which rely on intramolecular cyclization to liberatea drug substance and a lactam derivative have been described where theliberated drugs are alcohols, phenols, and primary and secondary amines.For alcohols see, Saari et al., J. Med. Chem., 33, pp. 2590-2595 (1990).For phenols see, Saari et al., J. Med. Chem., 33, pp. 97-101 (1990). Foramines see, Borchardt et al., Pharm. Sci., 86, pp. 757-767 (1997).

Any of the preferred embodiments recited herein, including thoseembodiments in the above species, may define formula (I) individually orbe combined to produce a preferred embodiment of this invention.

Abbreviations which are used in the schemes, preparations and theexamples that follow are:

-   THF: tetrahydrofuran-   DMF: N,N,-dimethylformamide-   EtOAc: ethyl acetate-   AcOH: acetic acid-   NMM: N-methylmorpholine-   NMP: N-methylpyyrolidinone-   EtOH: ethanol-   t-BuOH: tert-butanol-   Et₂O: diethyl ether-   DMSO: dimethyl sulfoxide-   DCCA: dichloroacetic acid-   DIEA: diisopropylethylamine-   MeCN: acetonitrile-   TFA: trifluoroacetic acid-   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene-   DEAD: diethyl azodicarboxylate-   HOBt: 1-hydroxybenzotriazole hydrate-   HOAt: 1-hydroxy-7-azabenzotriazole-   EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   Boc: tert-butyloxycarbonyl-   Boc₂O: di-tert-butyldicarbonate-   Cbz: benzyloxycarbonyl-   Cbz-Cl: benzyl chloroformate-   Fmoc: 9-fluorenyl methyloxycarbonyl-   SEM: silylethoxymethyl-   TBAF: tetrabutylammonium fluoride-   Chg: cyclohexylglycine-   t-BG: tert-butylglycine-   mCBPA: 3-chloroperoxybenzoic acid-   DAST: (diethylamino)sulfur trifluoride-   TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical-   PyBOP: tris(pyrrolidino)bromophosphonium hexafluorophosphate-   TBTU or HATU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate-   DMAP: 4-dimethylaminopyridine-   AIBN: 2,2′-azobisisobutyronitrile-   rt or RT: room temperature-   ON: overnight-   ND: not determined-   MS: mass spectrometry-   LC: liquid chromatography    General Synthetic Methodology:

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Advantageously, these compounds areconveniently synthesized from readily available starting materials.Schemes 1-17 below illustrate synthetic routes to the compounds of thepresent invention.

As can be appreciated by the skilled artisan, the synthetic schemesshown are not intended to comprise a comprehensive list of all means bywhich the compounds described and claimed in this application may besynthesized. Other equivalent schemes, which will be readily apparent tothe ordinary skilled organic chemist, may alternatively be used tosynthesize various portions of the molecule as illustrated by thegeneral schemes below. Additionally, the various synthetic stepsdescribed above may be performed in an alternate sequence or order togive the desired compounds. Other equivalent schemes, which will bereadily apparent to the ordinary skilled organic chemist, mayalternatively be used to synthesize various portions of the molecule asillustrated by the general schemes below, and the preparative examplesthat follow.

Scheme 1 above provides a general route for the preparation of compoundsof formula I and IA-1, wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂, R₂,R₄, and R₇ are H, and R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀R_(10′),R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, R₁₅, R₁₆, R₁₈, R_(18′), A, and U are asdescribed in any of the embodiments herein. As would be recognized byskilled practitioners, other suitable and commercially availablecoupling reagents may be used to prepare intermediates 3, 5, 7, and 10.Additionally, it will be recognized that the commercially available Cbzprotected amino acids represented by, for instance, Cbz-R₁—OH, mayalternatively be substituted with the commercial t-Boc protected aminoacids. Suitable deprotection conditions to remove the Boc protectinggroups are known to those skilled in the art. Likewise the oxidation ofintermediate 10 to compounds of formula IA-1 may be accomplished usingother suitable conditions known to the skilled artisan. Intermediate 2may be prepared according to the procedures described by Schoellkopf, etal., Justus Liebigs Ann. Chem. GE, pp. 183-202 (1976) and Stemple etal., Organic Letters, 2(18), pp. 2769-2772 (2000). Intermediate pyrroleacid 9 may be prepared according to the methods described in the schemesbelow starting from commercially available starting materials.

Scheme 2 above provides a general route for the preparation of compoundsof formula I and IA-2 wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂, R₁₈ isabsent and R_(18′) is ═O, U is a bond, A is —C(R₁₂)(R_(12′))-T-R₁₃wherein R₁₂ is absent, R_(12′) is ═O, T is a bond and R₁₃ is R₁₉, R₁₉ isa (C1-C12)-aliphatic- with one carbon atom replaced by an NR₁₉substituent, R₁₉ is hydrogen, x is preferably 2-4, R₂, R₄, and R₇ are H,and R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₂,R_(12′), R₁₄, R₁₅, and R₁₆ are as described in any of the embodimentsherein. The preparation of compounds of formula I and IA-2, wherein R₁₃is different than that depicted in scheme 2, may be accomplished insimilar fashion by acylation of the pyrrole anion using othercommercially available acid chlorides. As would be recognized by skilledpractitioners, other suitable and commercially available couplingreagents may be used to prepare intermediate 14. Likewise the oxidationof intermediate 14 may be accomplished using other suitable conditionsknown to the skilled artisan.

Scheme 3 above provides a general route for the preparation of compoundsof formula I and IA-3 wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂, R₁₈ isabsent and R_(18′) is ═O, U is a bond, A is —C(R₁₂)(R_(12′))-T-R₁₃wherein R₁₂ is hydrogen, R_(12′) is CH, T is oxygen and R₁₃ is —C(O)R′,R₂, R₄, and R₇ are H, and R′, R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀,R_(10′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, R₁₅, and R₁₆ are as describedin any of the embodiments herein. Condensation of the pyrrole 16 withparaformaldehyde is accomplished according to the procedures listed inPCT publication WO 97/41132. The preparation of compounds of formula Iand IA-2, wherein R₁₂ is hydrogen, R_(12′) is (C2-C6)-aliphatic- may beaccomplished in similar fashion by substituting the appropriate aldehydefor paraformaldehyde in the conversion of 16 to 17. As would berecognized by skilled practitioners, other suitable and commerciallyavailable coupling reagents may be used to prepare intermediate 20.Likewise the oxidation of intermediate 20 may be accomplished usingother suitable conditions known to the skilled artisan.

Scheme 4 above provides a general route for the preparation of compoundsof formula I and IA-4 and IA-5 wherein V is —C(O), W is—C(O)C(O)—N(R₆)₂, R₁₈ is absent and R_(18′) is ═O, U is a bond, A is—C(R₁₂)(R_(12′))-T-R₁₃ wherein R₁₂ is hydrogen, R_(12′) is CH, T isoxygen and R₁₃ is —P(O)(OR′)₂, R′ is benzyl (IA-4) or hydrogen (IA-5),R₂, R₄, and R₇ are H, and R′, R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀,R_(10′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, R₁₅, and R₁₆ are as describedin any of the embodiments herein. Pyrrole alcohol 17 (prepared bymethods described above in scheme 3) is converted to chloride 18 withthionyl chloride followed by displacement with potassium dibenzylphosphate to give phosphate ester 22 all according to the procedureslisted in PCT publication WO 97/41132. Mild acid hydrolysis of thet-butyl ester followed by the coupling conditions and oxidationdescribed in scheme 3 above gives compound IA-4. Hydrogenolysis ofdibenzyl ester IA-4 using standard palladium catalysis gives freephosphonooxy acid IA-5. The preparation of compounds of formula IA-4,wherein R′ is other than benzyl may be accomplished in similar fashionby using the appropriate phosphate reagent for the conversion of 21 to22. As would be recognized by skilled practitioners, other suitable andcommercially available coupling reagents may be used to prepareintermediate 24. Likewise the oxidation of intermediate 24 and thehydrogenolysis of IA-4 may be accomplished using other suitableconditions known to the skilled artisan.

Scheme 5 above provides a general route for the preparation of compoundsof formula I and IA-6 wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂, R₁₈ isabsent and R_(18′) is ═N(OR′), U is a bond, R₁₆ is R′, A is hydrogen,R₂, R₄, and R₇ are H, R′, R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀,R_(10′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, and R₁₅, are as described inany of the embodiments herein. Pyrrole acid 25 (prepared by methodsdescribed above in scheme 3 and below in scheme 6) is esterfied to giveSEM ester 26. Protection of the pyrrole nitrogen according to theprocedure in J. Chem. Soc. Perkin Trans. 1, pp. 2181-2186 (1986)provides intermediate 27. Condensation with hydroxylamine (oralkylhydroxyl amine wherein R₁₈ is absent and R_(18′) is ═N(OR′)),accomplished according to the procedure in J. Org. Chem., pp. 5917-5921(1992), gives oxime 28. TBAF deprotection of both silyl based protectinggroups according to the procedure described in J. Chem. Soc. PerkinTrans. (1), pp. 2181-2186 (1986), gives pyrrole oxime acid 29. Finalcoupling and oxidation are accomplished according to the procedureslisted above in schemes 1, 3, and 5. As would be recognized by skilledpractitioners, other suitable and commercially available couplingreagents may be used to prepare intermediate 30. Likewise the oxidationof intermediate 30 to IA-6 may be accomplished using other suitableconditions known to the skilled artisan.

Scheme 6 above provides a general route for the preparation of startingpyrrole acid 35, wherein R₁₄ and R₁₅ are methyl, A is H, R₁₈ is absent,R_(18′) is ═O, U is a bond and R₁₆ is methyl. It will be appreciated bythose skilled in the art that other pyrrole analogs of interest may besynthesized by modifications of scheme 6.

Scheme 7 above provides a general route for the preparation of compoundsof formula I and IA-7 wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂, R₁₈ isabsent and R_(18′) is ═N(R′), U is a bond, R₁₆ is R′, A is hydrogen, R₂,R₄, and R₇ are H, R′, R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′),R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, and R₁₅, are as described in any of theembodiments herein. Protected pyrrole ester 27 (prepared by methodsdescribed above in scheme 5 and scheme 6) is condensed with anappropriate amine, according to the procedure in J. Chem. Soc. Chem.Commun., (6) pp. 634-635 (1986), to give imine 36. TBAF deprotection ofboth silyl based protecting groups according to the procedure describedin J. Chem. Soc. Perkin Trans. (1), pp. 2181-2186 (1986), gives pyrroleimine acid 37. Final coupling and oxidation are accomplished accordingto the procedures listed above in schemes 1, 3, and 5. As would berecognized by skilled practitioners, other suitable and commerciallyavailable coupling reagents may be used to prepare intermediate 38.Likewise the oxidation of intermediate 38 to IA-7 may be accomplishedusing other suitable conditions known to the skilled artisan.

Scheme 8 above provides a general route for the preparation of compoundsof formula I and IA-8 wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂, R₁₈ isabsent and R_(18′) is ═CH₂, U is nitrogen, R₁₆ is R′ wherein R′ isacetyl, A is hydrogen, R₂, R₄, and R₇ are H, R₁, R₃, R₅, R_(5′), R₆, R₉,R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, and R₁₅, are asdescribed in any of the embodiments herein. Condensation of 27 withhydroxylamine using the procedure described in J. Org. Chem., pp.5917-5921 (1992), gives oxime 39. Oxime acylation with acetic anhydridefollowed by thermal rearrangement in pyridine, according to theprocedure described in Leibigs Ann. Chem., (12), pp. 2065-2080 (1986),gives enamide 41. TBAF deprotection of both silyl based protectinggroups according to the procedure described in J. Chem. Soc. PerkinTrans. (1), pp. 2181-2186 (1986), gives pyrrole acid 42. Final couplingand oxidation are accomplished according to the procedures listed abovein schemes 1, 3, 5, and 7. As would be recognized by skilledpractitioners, other suitable and commercially available couplingreagents may be used to prepare intermediate 43. Likewise the oxidationof intermediate 43 to IA-8 may be accomplished using other suitableconditions known to the skilled artisan.

Scheme 9 above provides a general route for the preparation of compoundsof formula I, IA-9, and IA-10 wherein V is —C(O), W is —C(O)C(O)—N(R₆)₂,R₁₈ is absent and R_(18′) is ═CH₂, U is oxygen, R₁₆ is —P(O)(OR′)₂wherein R′ is benzyl (IA-9) or hydrogen (IA-10), A is hydrogen, R₂, R₄,and R₇ are H, R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁,R_(11′), R₁₂, R_(12′), R₁₄, and R₁₅, are as described in any of theembodiments herein. The enolate of protected pyrrole ester 27 (preparedas described in the preceding schemes wherein R₁₆ is methyl) isgenerated with LDA and reacted with dibenzylchlorophosphate according tothe method described in Tet. Lett., pp. 4275-4277 (2003) to give enolphosphate 44. It will be appreciated by those skilled in the art thatother enol phosphates of interest may be prepared by the same procedureby adjusting the starting chlorophosphate reagent used. TBAFdeprotection of both Silyl based protecting groups according to theprocedure described in J. Chem. Soc. Perkin Trans. (1), pp. 2181-2186(1986), gives pyrrole acid 45. Final coupling and oxidation areaccomplished according to the procedures listed in any of the schemesabove. As would be recognized by skilled practitioners, other suitableand commercially available coupling reagents may be used to prepareintermediate 46. Hydrogenolysis of dibenzyl ester IA-9 using standardpalladium catalysis gives free enol phosphonooxy acid IA-10. Likewisethe oxidation of intermediate 24 and the deprotection of IA-9 may beaccomplished using other suitable conditions known to the skilledartisan.

Scheme 10 above provides a general route for the preparation ofcompounds of formula I and IA-11 wherein V is —C(O), W is—C(O)C(O)—N(R₆)₂, R₁₈ is absent and R_(18′) is ═CH₂, U is oxygen, R₁₆ is—C(O)R′, A is hydrogen, R₂, R₄, and R₇ are H, R₁, R₃, R₅, R_(5′), R₆,R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, R₁₅, and R₁₆,are as described in any of the embodiments herein. The enolate ofprotected pyrrole ester 27 (prepared as described in the precedingschemes wherein R₁₆ is methyl) is generated with LDA and reacted with asuitable acyl chloride to give enol ester 47. TBAF deprotection of bothsilyl based protecting groups according to the procedure described in J.Chem. Soc. Perkin Trans. (1), pp. 2181-2186 (1986), gives pyrrole acid48. Final coupling and oxidation are accomplished according to theprocedures listed in any of the schemes above. As would be recognized byskilled practitioners, other suitable and commercially availablecoupling reagents may be used to prepare intermediate 48. Likewise theoxidation of intermediate 48 may be accomplished using other suitableconditions known to the skilled artisan. Enol ethers wherein R₁₈ isabsent and R_(18′) is ═CH₂, U is oxygen and R₁₆ is —R′ may also beprepared according to the methods listed in scheme 10. For instance toprepare the enol ether analog wherein R₁₆ is methyl, the pyrrole enolategenerated from LDA treatment of 27 could be reacted with dimethylsulfate and then carried through the same synthetic sequence describedabove.

Scheme 11 above provides a general route for the preparation ofcompounds of formula I and IA-12 wherein V is —C(O), W is—C(O)C(O)—N(R₆)₂, are optionally taken together with the carbon atom towhich they are bound to form a 5- to 7-membered saturated ring system;wherein the R₁₈ and R_(18′) atoms bound to the carbon atom are O; U is abond, R₁₆ is —R′, A is hydrogen, R₂, R₄, and R₇ are H, R′, R₁, R₃, R₅,R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄,R₁₅, and R₁₆, are as described in any of the embodiments herein. Thepyrrole nitrogen in intermediate 11 (prepared as described in thepreceding schemes) is Boc protected under standard conditions to giveBOC-protected pyrrole ester 50. Acid catalyzed condensation with anappropriate diol according to the method described in J. Org. Chem. pp.2663-2669 (1984), gives ketal 52 which is hydrolized under basicconditions to give the pyrrole acid 53. Final coupling and oxidation areaccomplished according to the procedures listed in any of the schemesabove. As would be recognized by skilled practitioners, other suitableand commercially available coupling reagents may be used to prepareintermediate 54. Likewise the oxidation of intermediate 54 may beaccomplished using other suitable conditions known to the skilledartisan.

Scheme 12 above in combination with scheme 1 above provides a generalroute for the preparation of compounds of formula I and IH wherein V is—C(O), W is —C(O)C(O)—N(R₆)₂, R₂, R₄, and R₇ are H, and R₁, R₃, R₅,R_(5′), R₆, R₉, R_(9′), R₁₁, R_(11′), R₁₂, R_(12′), R₁₄, R₁₅, R₁₆, R₁₈,R_(18′), n, A, U, Z, and Z′ are as described in any of the embodimentsherein. Scheme 12 above in combination with scheme 1 also provides ageneral route for the preparation of compounds of formula I and IK usingmodifications (e.g. other appropriate commercially available startingmaterials) known to those skilled in the art.

Scheme 13 above in combination with scheme 1 above provides a generalroute for the preparation of compounds of formula I and IK wherein V is—C(O), W is —C(O)C(O)—N(R₆)₂, R₂, R₄, and R₇ are H, R₁₀, and R_(10′) arefluoro, and R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₁, R_(11′), R₁₂,R_(12′), R₁₄, R₁₅, R₁₆, R₁₈, R_(18′), A, and U, are as described in anyof the embodiments herein.

Scheme 14 above provides a general route for the preparation ofcompounds of formula I, IL, and IL-1 wherein V is —C(O), W is—C(O)C(O)—N(R₆)₂, R₂, R₄, R₇, R₉, R_(9′), R_(10′), R₁₁, and R_(11′), areH, R_(10′) is OR′, and R₁, R₃, R₅, R_(5′), R₆, R₁₄, R₁₅, R₁₆, R₁₈,R_(18′), A, and U, are as described in any of the embodiments herein. Aswould be appreciated by any skilled practitioner, compound 67 may becarried on to compounds of formula IL-1 by routine methods.Additionally, other suitable and commercially available couplingreagents may be used to prepare intermediates 64, 65, 67, and 68.Likewise, the oxidation of intermediate 68 to compounds of formula IL-1may be accomplished using other suitable conditions known to the skilledartisan.

Scheme 15 above, depicts an alternative approach to preparing compoundsof formula IL and IL-1 of this invention wherein V is —C(O), W is—C(O)C(O)—N(R₆)₂, R₂, R₄, R₇, R₉, R_(9′), R₁₀, R_(11′), and R₁₁, are H,R_(10′) is OR′, and R₁, R₃, R₅, R_(5′), R₆, R₁₄, R₁₅, R₁₆, R₁₈, R_(18′),A, and U, are as described in any of the embodiments herein. In thisapproach, a 4-hydroxyproline derivative 69 is reacted with acommercially available R′-halide (such an aryl chloride), represented byR′—X, in the presence of a suitable base (such as potassium t-butoxide)to provide a compound 70. As would be appreciated by any skilledpractitioner, compound 70 may be carried on to compounds of formula IE-1by routine methods. Additionally, other suitable and commerciallyavailable coupling reagents may be used to prepare intermediates 72, 73,74, and 75. Likewise, the oxidation of intermediate 75 to compounds offormula IL-1 may be accomplished using other suitable conditions knownto the skilled artisan.

Scheme 16 in combination with scheme 1 above provides a general routefor the preparation of compounds of formula IM, and IM-1 wherein V is—C(O), W is —C(O)C(O)—N(R₆)₂, R₂, R₄, R₇, R₉, R_(9′), R_(10′), andR_(11′), are H, R₁₀ and R₁₁ are taken together with the ring atoms towhich they are bound to form a ring system as defined in any of theembodiments and R₁, R₃, R₅, R_(5′), R₆, R₁₄, R₁₅, R₁₆, R₁₈, R_(18′), A,and U, are as described in any of the embodiments herein. Bicyclicstarting materials such as compound 76 may be any commercially availablereagents of interest or may be synthesized according to literaturemethods known to the skilled artisan. After coupling of 76 tointermediate 2, resulting intermediate 80 may be carried on to compoundsof formula IM-1 by the methods described in scheme 1. Scheme 16 incombination with scheme 1

Compounds of this invention represented by formula IN may also beprepared from commercially available amino acid derivatives by the routedescribed in schemes 1 and 16 above. If a starting amino acid analogueof interest is not commercially available it may be prepared accordingto literature methods known to those skilled in the art.

Scheme 17 above provides a synthetic route for the preparation ofCbz-protected azabicyclo[2.2.1]heptane-3-carboxylic acid, compound 83and the corresponding t-butyl ester, compound 84. The free acid 83 maybe further elaborated by the route defined in scheme 1 above to preparecompounds of formula I and IO.

The preparation of various other optionally substituted multicyclicazaheterocyclyls intermediates to prepare compounds of formulae I and INvia schemes 1, 14 or 15 above, may be accomplished by the methodsdescribed in PCT publication No. WO 02/18369 and references citedtherein.

Various 3, 4, and 5-substituted proline analogues may either bepurchased commercially or prepared according to known literatureprocedures. For instance, for compounds of formula I wherein R_(9′) is(C1-C12)-aliphatic-, the starting 3-substituted proline analogues may beprepared according to the method of Holladay, M. W. et al., J. Med.Chem., 34, pp. 457-461 (1991). For compounds of formula I wherein eitherR_(9′), R_(10′), or R_(11′) are cyclohexyl and R₉, R₁₀, or R₁₁ arehydrogen, the cyclohexyl proline intermediates may be prepared byplatinum oxide reduction of the commercially available phenylsubstituted proline analogues. Such reduction conditions are well knownto those skilled in the art. For compounds of formula I wherein R_(9′)is (C1-C12)-aliphatic- and R_(10′) is (C1-C12)-aliphatic-, the starting3,4-disubstituted proline analogues may be prepared according to themethod of Kanamasa, S. et al., J. Org. Chem., 56, pp. 2875-2883 (1991).In each of the syntheses involving 3, 4, or 5-substituted prolines or3,4-disubstituted prolines, the intermediates may be further elaboratedby the routes defined above in schemes 1, 14, or 15 to prepare compoundsof formula I.

Accordingly, one embodiment of this invention provides a process forpreparing a compound of formula I, as defined in any of the embodimentsherein, comprising the step of: reacting a compound of formula VII inthe presence of a compound of formula VIII to provide a compound offormula IX:

wherein:R₂₁ is an amine protecting group, a P3-residue of an HCV proteaseinhibitor described herein, or a P4-P3-residue of an HCV proteaseinhibitor as described herein, and wherein the P3 and the P4-P3 residuesare optionally protected with an amino-terminal capping group;R₂₀ is a carboxy protecting group or a P1 residue of an HCV proteaseinhibitor described herein, wherein the P1 residue is optionallyprotected with a carboxy terminal protecting group or with W. R′ is asdefined in any of the embodiments herein. X is an appropriate leavinggroup. As would be appreciated by skilled practitioners, an appropriateleaving group may be generated in situ.

In an alternative embodiment, the 4-hydroxy group in formula VII may beconverted to a leaving group. In such an embodiment, X is a nucleophilicoxygen which reacts with VII to provide IX.

As used herein, P1, P3, P4 refer to the residues of an HCV proteaseinhibitor as defined in the art and as are well known to skilledpractitioners.

The compound of formula IX may be carried on to a compound of formula Iaccording to the methods described herein.

Although certain exemplary embodiments are depicted and described below,it will be appreciated that compounds of this invention can be preparedaccording to the methods described generally above using appropriatestarting materials generally available to one of ordinary skill in theart.

Another embodiment of this invention provides a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof. According to a preferred embodiment, thecompound of formula I is present in an amount effective to decrease theviral load in a sample or in a patient, wherein said virus encodes aserine protease necessary for the viral life cycle, and apharmaceutically acceptable carrier.

If pharmaceutically acceptable salts of the compounds of this inventionare utilized in these compositions, those salts are preferably derivedfrom inorganic or organic acids and bases. Included among such acidsalts are the following: acetate, adipate, alginate, aspartate,benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate,camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth.

Also, the basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The compounds utilized in the compositions and methods of this inventionmay also be modified by appending appropriate functionalities to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being.

Such pharmaceutical compositions of the present invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between about 0.5 and about 75 mg/kg body weight per dayof the protease inhibitor compounds described herein are useful in amonotherapy for the prevention and treatment of antiviral, particularlyanti-HCV mediated disease. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 5 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Preferably, such preparationscontain from about 20% to about 80% active compound.

When the compositions of this invention comprise a combination of acompound of formula I and one or more additional therapeutic orprophylactic agents, both the compound and the additional agent shouldbe present at dosage levels of between about 10 to 100%, and morepreferably between about 10 to 80% of the dosage normally administeredin a monotherapy regimen.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions may be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferred are pharmaceutical compositions formulated for oraladministration.

In one embodiment, the compositions of this invention additionallycomprise another agent, preferably a cytochrome P-450 inhibitor. Suchcytochrome P-450 inhibitors include, but are not limited to, ritonavir.

In another embodiment, the compositions of this invention additionallycomprise another anti-viral agent, preferably an anti-HCV agent. Suchanti-viral agents include, but are not limited to, immunomodulatoryagents, such as α-, β-, and γ-interferons, pegylated derivatizedinterferon-α compounds, and thymosin; other anti-viral agents, such asribavirin, amantadine, and telbivudine; other inhibitors of hepatitis Cproteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors ofother targets in the HCV life cycle, including helicase and polymeraseinhibitors; inhibitors of internal ribosome entry; broad-spectrum viralinhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDHinhibitors disclosed in U.S. Pat. Nos. 5,807,876 and 6,498,178,mycophenolic acid and derivatives thereof); inhibitors of cytochromeP-450, such as ritonavir, or combinations of any of the above.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of active ingredients will also depend upon the particulardescribed compound and the presence or absence and the nature of theadditional anti-viral agent in the composition.

According to another embodiment, the invention provides a method fortreating a patient infected with a virus characterized by a virallyencoded serine protease that is necessary for the life cycle of thevirus by administering to said patient a pharmaceutically acceptablecomposition of this invention. Preferably, the methods of this inventionare used to treat a patient suffering from a HCV infection. Suchtreatment may completely eradicate the viral infection or reduce theseverity thereof. More preferably, the patient is a human being.

In an alternate embodiment, the methods of this invention additionallycomprise the step of administering to said patient an anti-viral agentpreferably an anti-HCV agent. Such anti-viral agents include, but arenot limited to, immunomodulatory agents, such as α-, β-, andγ-interferons, pegylated derivatized interferon-α compounds, andthymosin; other anti-viral agents, such as ribavirin, amantadine, andtelbivudine; other inhibitors of hepatitis C proteases (NS2-NS3inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in theHCV life cycle, including but not limited to helicase and polymeraseinhibitors; inhibitors of internal ribosome entry; broad-spectrum viralinhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDHinhibitors disclosed in U.S. Pat. Nos. 5,807,876 and 6,498,178,mycophenolic acid and derivatives thereof); inhibitors of cytochromeP-450, such as ritonavir, or combinations of any of the above.

Such additional agent may be administered to said patient as part of asingle dosage form comprising both a compound of this invention and anadditional anti-viral agent. Alternatively the additional agent may beadministered separately from the compound of this invention, as part ofa multiple dosage form, wherein said additional agent is administeredprior to, together with or following a composition comprising a compoundof this invention.

In yet another embodiment the present invention provides a method ofpre-treating a biological substance intended for administration to apatient comprising the step of contacting said biological substance witha pharmaceutically acceptable composition comprising a compound of thisinvention. Such biological substances include, but are not limited to,blood and components thereof such as plasma, platelets, subpopulationsof blood cells and the like; organs such as kidney, liver, heart, lung,etc; sperm and ova; bone marrow and components thereof, and other fluidsto be infused into a patient such as saline, dextrose, etc.

According to another embodiment the invention provides methods oftreating materials that may potentially come into contact with a viruscharacterized by a virally encoded serine protease necessary for itslife cycle. This method comprises the step of contacting said materialwith a compound according to the invention. Such materials include, butare not limited to, surgical instruments and garments (e.g. clothes,gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratoryinstruments and garments (e.g. clothes, gloves, aprons, gowns, masks,eyeglasses, footwear, etc.); blood collection apparatuses and materials;and invasive devices, such as shunts, stents, etc.

In another embodiment, the compounds of this invention may be used aslaboratory tools to aid in the isolation of a virally encoded serineprotease. This method comprises the steps of providing a compound ofthis invention attached to a solid support; contacting said solidsupport with a sample containing a viral serine protease underconditions that cause said protease to bind to said solid support; andeluting said serine protease from said solid support. Preferably, theviral serine protease isolated by this method is HCV NS3-NS4A protease.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

EXAMPLES

¹H-NMR spectra were recorded at 500 MHz using a Bruker AMX 500instrument. Mass spec. samples were analyzed on a MicroMass ZQ orQuattro II mass spectrometer operated in single MS mode withelectrospray ionization. Samples were introduced into the massspectrometer using flow injection (FIA) or chromatography. Mobile phasefor all mass spec. analysis consisted of acetonitrile-water mixtureswith 0.2% formic acid as a modifier.

As used herein, the term “R_(t)(min)” refers to the HPLC retention time,in minutes, associated with the compound. The HPLC retention timeslisted were either obtained from the mass spec. data or using thefollowing method:

-   Instrument: Hewlett Packard HP-1050;-   Column: YMC C₁₈ (Cat. No. 326289C46);-   Gradient/Gradient Time: 10-90% CH₃CN/H2O over 9 minutes, then 100%    CH₃CN for 2 minutes;-   Flow Rate: 0.8 ml/min;-   Detector Wavelength: 215 nM and 245 nM.

Chemical naming for selected compounds herein was accomplished using thenaming program provided by CambridgeSoft Corporations ChemDraw Ultra®,version 7.0.1.

Example 1 3-Acetyl-4,5-dimethyl-2-pyrrole carboxylic acid (35)

A solution of sodium nitrite (36.9 g, 0.534 mol) in 70 mL of water wasadded dropwise to a stirred solution of ethylacetoacetate (70 g, 0.538mol) in 1401 mL of glacial acetic acid at 0° C. After the addition wascomplete, the light yellow reaction mixture was allowed to warm to roomtemperature. After 30 minutes, all the starting material had beenconsumed, the reaction was quenched with 350 mL of water and extractedwith ethyl acetate (2×125 mL). The organic extracts were combined andwashed with water (2×125 mL) and saturated sodium hydrogen carbonateaqueous solution (2×105 mL). The organic layer was dried with sodiumsulfate and concentrated in vacuo to give 84.2 g (98%) ofethyl-2-hydroxyimino-3-oxobutanoate 31 as a pale yellow oil. ¹H NMR(CDCl₃) δ 10.3 (s, 1H), 4.2 (q, 2H), 2.3 (s, 3H), 1.3 (t, 3H) ppm.

Crushed sodium (12.4 g, 0.540 mol) was added to a solution of 2-butanone(48.2 mL, 0.538 mol) and ethyl formate (43.47 mL, 0.538 mol) in dryether (540 mL) with vigorous mechanical stirring over a period of 1 h,during which time the mixture was chilled in an ice-salt bath. Themixture was then stirred at room temp. for 14 h. After cooling thereaction mixture to 4° C. for a few hours, the precipitated sodium saltwas obtained by filtration and washed thoroughly with cold, dry ether toafford 49.3 g (75%) of the desired sodium salt of2-Methyl-3-oxobutyraldehyde 32. ¹H NMR (DMSO-d₆) δ 9.1 (s, 1H), 1.9 (s,3H), 1.3 (s, 3H) ppm.

Sodium salt 32 (49.3 g, 0.404 mol) and oxime 31 (64.23, 0.404 mol) werestirred in 300 mL of 70% acetic acid/30% water and warmed to 50° C. Zincpowder (42.21 g, 0.646 mol) was added portion-wise over 30 minutesmaintaining the temperature below 100° C. When the addition wascomplete, the suspension was refluxed for 15 minutes, then poured into 4L of ice-water. After a short time, the product precipitated out togive, after filtration, 30.1 g (45%) of the desiredethyl-4,5-dimethyl-2-pyrrole carboxylate 33. ¹H NMR (CDCl₃) δ 9.0 (bs,1H), 6.7 (s, 1H), 4.3 (q, 2H), 2.3 (s, 3H), 2.0 (s, 3H), 1.3 (t, 3H)ppm.

To a solution of aluminum chloride (50.19 g, 0.376 mol) in drydichloroethane (580 mL) at 25° C. was added slowly acetic anhydride(17.75 mL, 0.188 mol). The resulting mixture was stirred at room temp.for 10 minutes, then a solution of pyrrole 33 (10.49 g, 0.0627 mol) indichloroethane (30 mL) was added and the reaction mixture was stirred atroom temp. for 2 h. After an additional 3 h at 80° C., the mixture waspoured into ice water and extracted with dichloromethane. The organiclayer was dried with anhy. sodium sulfate and concentrated in vacuo toan orange residue. Short plug filtration over silica gel (30% ethylacetate/70% hexanes) gave 7.5 g (60%) ofethyl-3-acetyl-4,5-dimethyl-2-pyrrole carboxylate 34. ¹H NMR (CDCl₃) δ9.0 (bs, 1H), 4.3 (q, 2H), 2.7 (s, 3H), 2.1 (s, 3H), 1.9 (s, 3H), 1.3(t, 3H) ppm.

A mixture of pyrrole ester 34 (8.2 g, 0.0392 mol), in ethanol and 100 mLof 10% potassium hydroxide were refluxed for 1 h. The mixture was cooledand concentrated in vacuo to an oil. Water was added to the oil, themixture acidified with dilute HCl and extracted with ether. The organicphase was dried with anhy. sodium sulfate and concentrated in vacuo to asolid residue. The compound was recrystallized in 80 mL of ethanol togive 5.8 g of pure 3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 35 asa solid. ¹H NMR (DMSO-d₆) δ 2.5 (s, 3H), 2.2 (s, 3H), 2.0 (s, 3H) ppm.

1. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R₉ and R_(9′)are each independently: hydrogen-, (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to three aliphaticcarbon atoms in each of R₉ and R_(9′) are optionally replaced by O, N,NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₉and R_(9′) is independently and optionally substituted with up to 3substituents independently selected from J; J is halogen, —OR′, —NO₂,—CN, —CF₃—OCF₃, —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy,1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂, —SO₃R′,—C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)₂, —C(O)CH₂C(O)R′,—C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂,—C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′,—N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′,—N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,—N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′,—OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′); wherein; eachR′ is independently selected from the group consisting of: hydrogen-,(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-,[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,(C5-C10)-heteroaryl-, and (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;wherein up to 5 atoms in R′ are optionally and independently substitutedwith J; wherein two R′ groups bound to the same atom optionally form a5- to 6-membered aromatic or a 3- to 7-membered saturated or partiallyunsaturated ring system having up to 3 heteroatoms independentlyselected from the group consisting of N, NH, O, S, SO, and SO₂, whereinsaid ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has upto 3 substituents selected independently from J; R₁₀, R_(10′), R₁₁, andR_(11′) are each independently: hydrogen-, (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein any ring is optionallyfused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or(C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms in each ofR₁₀, R_(10′), R₁₁, and R_(11′) are optionally replaced by a heteroatomselected from O, NH, S, SO, or SO₂ in a chemically stable arrangement;wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is independently andoptionally substituted with up to 3 substituents independently selectedfrom J; or R₁₀ is —OR′ and R_(10′) is H, or R₁₀ and R_(10′) are both—OR′ or —SR'; or R₁₀ and R_(10′) are both fluorine; or R₁₀ and R_(10′)are optionally taken together with the carbon atom to which they arebound to form a 5- to 7-membered saturated or partially unsaturated ringsystem; wherein the R₁₀ and R_(10′) atoms bound to the carbon atom areindependently C(H), N, NH, O, S, SO, or SO₂; wherein said ringoptionally contains up to 4 heteroatoms independently selected from thegroup consisting of N, NH, O, S, SO, and SO₂; wherein any atom isoptionally singly or multiply substituted with up to 2 substituentsselected independently from J; and wherein said ring is optionally fusedto a second ring selected from the group consisting of (C6-C10)aryl,(C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl,wherein said second ring has up to 3 substituents selected independentlyfrom J; or R₉ and R₁₀ are optionally taken together with the ring atomsto which they are bound to form a 5- to 6-membered aromatic or a 3- to7-membered saturated or partially unsaturated ring system up to 3heteroatoms independently selected from N, NH, O, S, SO, or SO₂; whereinsaid ring system is optionally substituted with up to 3 substituentsselected independently from J; or R₁₀ and R₁₁ are optionally takentogether with the ring atoms to which they are bound to form a 5- to6-membered aromatic or a 3- to 7-membered saturated or partiallyunsaturated ring system having up to 3 heteroatoms independentlyselected from N, NH, O, S, SO, or SO₂; wherein said ring is optionallysubstituted with up to 3 substituents selected independently from J; orR₉ and R₁₁ are optionally taken together with the ring atoms to whichthey are bound to form a bridged bicyclic saturated or partiallyunsaturated carbocyclic or heterocyclic ring system containing up to 10atoms; wherein said ring system is optionally substituted with up to 3substituents selected independently from J; wherein each heteroatom inthe heterocyclic ring system is selected from the group consisting of N,NH, O, S, SO, and SO₂; R₁ and R₃ are each independently:(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-,[(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,(C6-C10)-aryl-(C1-C12)aliphatic-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphaticcarbon atoms in each of R₁ and R₃ are optionally replaced by aheteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stablearrangement; wherein each of R₁ and R₃ is independently and optionallysubstituted with up to 3 substituents independently selected from J; R₂,R₄ and R₇ are each independently: hydrogen-, (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or(C6-C10)-aryl-(C1-C12)-aliphatic-; wherein up to two aliphatic carbonatoms in each of R₂, R₄ and R₇ are optionally replaced by a heteroatomselected from the group consisting of O, N, NH, S, SO, and SO₂ in achemically stable arrangement; wherein each of R₂, R₄ and R₇ isoptionally substituted with up to 3 substituents independently selectedfrom J; R₅ and R_(5′) are each independently hydrogen or(C1-C12)-aliphatic, wherein any hydrogen is optionally replaced withhalogen; wherein any terminal carbon atom of R₅ is optionallysubstituted with sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R_(5′)is H, wherein said Ph or —CH₂Ph group is optionally substituted with upto 3 substituents independently selected from J; or R₅ and R_(5′)together with the atom to which they are bound optionally form a 3- to6-membered saturated or partially unsaturated ring having up to 2heteroatoms selected from the group consisting of N, NH, O, SO, and SO₂;wherein said ring is optionally substituted with up to 2 substituentsselected independently from J; W is:

wherein m is 0 or 1; wherein each R₆ is independently: hydrogen-,(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-cycloalkyl- or cycloalkenyl-, [(C3-C10)-cycloalkyl- orcycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphaticcarbon atoms in each R₆ is optionally replaced by a heteroatom selectedfrom O, NH, S, SO, or SO₂, in a chemically stable arrangement; whereinR₆ is optionally substituted with up to 3 J substituents; or two R₆groups, together with the nitrogen atom to which they are bound,optionally form a 5- to 6-membered aromatic or a 3- to 7-memberedsaturated or partially unsaturated ring system having up to 3heteroatoms independently selected from the group consisting of N, NH,O, S, SO, and SO₂, wherein said ring is optionally fused to a(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a(C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selectedindependently from J; wherein each R₈ is independently —OR′; or the R₈groups together with the boron atom, is a (C3-C10)-membered heterocyclicring having in addition to the boron up to 3 additional heteroatomsselected from the group consisting of N, NR′, O, SO, and SO₂; V is—C(O)—, —C(S)—, —S(O)—, or —S(O)₂—; A is hydrogen or—C(R₁₂)(R_(12′))-T-R₁₃; T is oxygen or a bond; R₁₂ and R_(12′) are eachindependently: hydrogen-, or (C1-C6)-aliphatic-; wherein up to twoaliphatic carbon atoms in each of R₁₂ and R_(12′) are optionallyreplaced by a heteroatom selected from the group consisting of O, N, NH,S, SO, and SO₂ in a chemically stable arrangement; or R₁₂ is absent andR_(12′) is ═O; R₁₃ is —C(O)R′, —P(O)(OR′)₂, —SO₃R′, —R′, or R₁₉; R₁₉ is:hydrogen, (C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphaticcarbon atoms in each R₁₉ is optionally replaced by a heteroatom selectedfrom O, NR₁₉, S, SO, or SO₂ in a chemically stable arrangement; whereinup to 3 aliphatic carbon atoms in each R₁₉ is optionally replaced with—C(O)—; wherein R₁₉ is optionally substituted with up to 3 Jsubstituents; wherein any NR₁₉, taken together with the nitrogen and acarbon adjacent to the nitrogen, optionally forms a 5- to 7-memberedring system, wherein said ring system optionally contains up to threeadditional heteroatoms selected from the group consisting of O, N, NH,S, SO, and SO₂ in a chemically stable arrangement; R₁₄ and R₁₅ areindependently halogen, —OR′, —OC(O)N(R′)₂, —NO₂, —CN, —CF₃, —OCF₃, —R′,1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′,—SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —C(S)R′,—C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, or—(CH₂)₀₋₂NHC(O)R′; R₁₆ is R′, —C(O)R′, —P(O)(OR′)₂ or —SO₃R′; U is O, N,or a bond; and R₁₈ and R_(18′) are optionally taken together with thecarbon atom to which they are bound to form a 5- to 7-membered saturatedor partially unsaturated ring system; wherein the R₁₈ and R_(18′) atomsbound to the carbon atom are independently O or N; wherein said ringoptionally contains up to 1 additional heteroatom selected from thegroup consisting of N, NH, O, S, SO, and SO₂; wherein any substitutableatom is optionally singly or multiply substituted with up to 2substituents selected independently from J; wherein said ring isoptionally fused to a second ring selected from the group consisting of(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a(C3-C10)heterocyclyl, wherein said second ring has up to 3 substituentsselected independently from J; provided that when R₁₈ and R_(18′) areoptionally taken together with the carbon atom to which they are boundto form a 5- to 7-membered saturated or partially unsaturated ringsystem, then R₁₆ is R′; or R_(18′) is ═O, ═CH₂, ═N(R′), or ═N(OR′) andR₁₈ is absent, provided that when R₁₈ is absent and R_(18′) is ═CH₂,then U is oxygen; and provided that when R₁₈ is absent and R_(18′) is═O, ═N(R′) or ═N(OR′), then U is a bond and R₁₆ is R′; and provided thatwhen R₁₈ is absent, R_(18′) is ═O, U is a bond and R₁₆ is R′, then A is—C(R₁₂)(R₁₂)-T-R₁₃; and a acceptable carrier, adjuvant or vehicle,wherein said composition is formulated for administration to a patient.2. The composition according to claim 1, wherein said compositioncomprises an additional agent selected from an immunomodulatory agent;an antiviral agent; a second inhibitor of HCV protease; an inhibitor ofanother target in the HCV life cycle; and a cytochrome P-450 inhibitor;or combinations thereof.
 3. The composition according to claim 1,wherein said immunomodulatory agent is α-, β-, or γ-interferon orthymosin; said antiviral agent is ribavirin, amantadine, or telbivudine;or said inhibitor of another target in the HCV life cycle is aninhibitor of HCV helicase, polymerase, or metalloprotease.
 4. Thecomposition according to claim 2, wherein said cytochrome P-450inhibitor is ritonavir.